High-powered microscopic view of H7N9 influenza virus. Scientist recently have detailed plans to modify the virus in the lab to explore its transmissibility factors.

The Center for Arms Control and Non-Proliferation, a Washington, DC, group that works to limit the spread of nuclear, chemical, and biological weapons, contends in a risk assessment report that "gain of function" (GOF) research on highly pathogenic avian influenza (HPAI) viruses poses a serious risk of triggering a deadly flu outbreak.

The report attempts to estimate the risk of accidental infection of a lab worker and ensuing transmission of the virus to others on public transportation. It concludes that 1 year of research by one lab poses a risk of releasing a virus that would cause between 180 and 1,100 deaths, and that research by additional labs and for longer periods would multiply this risk.

The assessment was written by Lynn C. Klotz, senior science fellow at the center and a former Harvard professor and biotechnology executive. The report is one of very few attempts thus far to estimate the risk associated with research that involves manipulating highly pathogenic avian flu viruses such as H5N1 to make them more transmissible in mammals. A major aim of such experiments is to identify dangerous mutations so that scientists can watch for them in circulating viruses.

Last year two teams of scientists published studies that involved generating mutant H5N1 viruses that showed airborne transmissibility in ferrets. The studies were published only after a prolonged controversy and scrutiny of the findings by the US National Science Advisory Board for Biodefense (NSABB), which was concerned that publishing the details would pose a risk of the intentional or accidental release of dangerous viruses.

The controversy led to a voluntary moratorium on GOF research on HPAI viruses.

As noted in the risk assessment, last month 22 virologists announced their intention to conduct GOF research on the H7N9 avian flu virus, which emerged this year in China and has caused 135 illnesses and 43 deaths so far. The virologists' plans include studies designed to identify mutations and gene combinations that lead to increased transmissibility of the virus in mammals, such as ferrets and guinea pigs.

Klotz's risk assessment is billed as a "likelihood-weighted consequence analysis," a standard method for assessing risk. The formula estimates the possible number of deaths associated with 1 year of research in one lab on the basis of three factors: the probability of a virus release, the probability that a releases leads to a pandemic, and the number of deaths in a pandemic.

The approach rests on a variety of assumptions. A key one is that the basic reproduction number for the novel virus—the number of new cases generated by each case introduced in an uninfected population—would be 2.0. Another is that the case-fatality rate (CFR) would be 10%. That is far higher than the approximately 2% seen in the 1918 flu pandemic, but much lower than the 60% CFR among known human H5N1 cases.

An additional assumption is that a pandemic would cause 100 million deaths worldwide, which is the high end of published estimates of the global toll in 1918. The number is based on the assumption that 15% of the world population of 7 billion would be infected, with a 10% CFR.

The estimate incorporates a recent report that four previously unreported lab-acquired infections occurred in US select-agent labs between 2004 and 2010. It also employs assumptions about the proportion of lab workers who use public transit (10%) and the numbers of people who would be exposed to an infected worker on buses and trains, among other things.

Using all these factors, Klotz comes up with the estimate that the risk associated with one lab in 1 year of GOF research would be anywhere between 180 and 1,100 deaths. With more labs doing such research, he writes, the risk would increase dramatically.

"Whatever number we are gambling with, it is clearly far too high a risk to human lives around the world, so this particular PPP [potential pandemic pathogen] research must be shut down," he concludes.

Nicholas Kelley, PhD, a research associate with the BioWatch program at the University of Minnesota's Center for Infectious Disease Research and Policy, which publishes CIDRAP News, said the risk assessment has some limitations but offers a starting point for discussions on how to estimate the risks of GOF research. Kelley was a coauthor of a major CIDRAP report on flu vaccines, published in 2011.

"I think some of the assumptions are well within the range of the assumptions we see for influenza," he said. "There are not a whole lot of these risk assessments out there, so I think it's a good start for a conversation on how to conduct these risk assessments."

Kelley said the assumed basic reproduction number of 2.0 is higher than the typical number for seasonal flu and for the 2009 pandemic but about what was seen in the 1918 pandemic.

As for the 10% CFR, he said government reports about severe pandemic scenarios typically cite a CFR of 2%. The 2009 pandemic CFR was much lower, as were the pandemics of 1957 and 1968. "It would be nice to see a simulation of a variety of CFRs and how that would affect the risk assessment," he added.

"These risk assessments get more useful the more all-encompassing they are; this primarily focused on infection leaving a lab based on transmission during transportation to and from work," Kelley commented. "There are other means of exposure. They make your model more complex but provide better insight into the risks associated with this kind of work."

"We need a lot more work to fully understand the risk of these studies," he said. "I'm glad some people are starting to conceptualize what some of these risks are and starting discussions on it."

See also:

Center for Arms Control report: The Human Fatality Burden of Gain of Function Flu Research: A Risk Assessment